Preparation of 3,5-Dioxo Hexanoate Ester in Two Steps

ABSTRACT

The invention discloses a method for the preparation of tert-butyl 6-chloro-3,5-dioxohexanoate from Meldrum&#39;s acid derivative and its use for the preparation of tert-butyl (4R,6S)-(6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate (BHA), Rosuvastatin and Atorvastatin.

The invention discloses a method for the preparation of tert-butyl6-chloro-3,5-dioxohexanoate from Meldrum's acid derivative and its usefor the preparation of tert-butyl(4R,6S)-(6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate (BHA),Rosuvastatin and Atorvastatin.

BHA is an intermediate in the preparation of Rosuvastatin andAtorvastatin, which are active pharmaceutical ingredients used inrespective drugs to treat high cholesterol and related conditions, andto prevent cardiovascular disease. BHA is prepared from a 3,5-dioxohexanoate ester.

EP 1024139 B discloses a method for preparation of BHA comprising areaction of an acetate ester with a hydroxybutyric acid derivative toget the intermediate 3,5-dioxo hexanoate ester.

Tetrahedron 55 (1999) 4783-4792 discloses the synthesis of 3,6- and5,6-dialkyl-4-hydroxy-2-pyrones with the help of Meldrum's acid.

WO 01/72706 A discloses a multistep method for the preparation of BHAand implicitly discloses a precursor, which is the condensation productof a beta-keto butyric acid derivative with meldrum's acid; thehydrolysis thereof provides the respective 3,5-dioxohexanoic acidderivative, the precursor of BHA. The advantages of the instantinvention compared to the process disclosed in WO 01/72706 A arediscussed below.

The known processes for the preparation of the intermediate 3,5-dioxohexanoate ester which is used in the preparation of BHA are multi stepprocedures involving metal containing bases. e.g. derived from lithiumor magnesium. There was a need for a simplified process for thepreparation of the intermediate 3,5-dioxo hexanoate ester, whichnecessitates less steps, no use of metal containing bases derived frommagnesium or lithium, and provides for higher yields and purer products,which can be isolated in an uncomplicated way. Surprisingly, using aMeldrum's acid intermediate, an efficient method was found.

The following abbreviations are used, if not otherwise stated:

In the following text, halogen means F, Cl, Br or I, preferably Cl, Bror I; more preferably Cl or Br; alkyl means linear and branched alkyl;unless otherwise specified.

Subject of the invention is a method (B) for the preparation of acompound of formula (II);

-   R1 is Cl, Br and CN;-   method (B) comprises a step (C) and a step (B);-   step (B) is done after step (C);-   step (C) comprises a reaction (C) of a compound of formula (VI) with    a compound (C) to provide a compound of formula (IV);

-   the compound (C) is selected from the group consisting of Cl₂, Br₂    and ClBr;-   step (B) comprises a reaction (B) of the compound of formula (IV),    which has been prepared in step (C), with a compound of formula (V)    in the presence of a base (B);

-   R1-IV and R3 are identical or different and independently from each    other Cl or Br;-   base (B) is selected from the group consisting of N(R4)(R5)R6,    1,4-diazabicyclo[2.2.2]octane, a hexamethyldisilazide, a C₁₋₄    alkoxide salt of, a C₁₋₁₀ carboxylate salt of, a carbonate salt of,    a hydrogen carbonate salt of, a phosphate salt of, a    monohydrogenphosphate salt of or a dihydrogenphosphate salt of Na,    of K or of Li, 1,8-diazabicyclo[5.4.0]undec-7-ene, NaNH₂, KNH₂, NaH,    KH, CaH₂, pyridine, pyridine substituted with 1 or 2 identical or    different substituents independently from each other selected from    the group consisting of methyl, ethyl and N(R14)R15; morpholine,    methylmorpholine, methylpiperidine, imidazol, benzimidazol,    2-methylimidazole, 4-methylimidazole, 2-ethylimidazole,    2-ethyl-4-methylimidazole, 2-isopropylimidazole, 2-phenylimidazole,    4-phenylimidazole, picoline, CsCO₃, NaOH, KOH, Ca(OH)₂, n-butyl    lithium (BuLi), sec-butyl lithium, tert-butyl lithium, hexyl    lithium, methyl lithium and mixtures thereof;-   R4, R5, R6 are identical or different and independently from each    other selected from the group consisting of H, C₁₋₁₅ alkyl, C₅₋₆    cycloalkyl, (C(R16)R17)_(m)N(R12)R13 and phenyl, with the proviso,    that at least one of the residues R4, R5 or R6 is not H;-   R12 and R13 are identical or different and independently from each    other H or C₁₋₁₅ alkyl;-   m is 2, 3, 4, 5 or 6;-   R14 and R15 are identical or different and independently from each    other methyl or ethyl;-   R16 and R17 are identical or different and independently from each    other selected from the group consisting of H, methyl and ethyl;-   with the proviso, that if R1 in formula (II) is CN, then-   step (B) comprises additionally a reaction (B-add), the reaction    (B-add) is done after the reaction (B), of the reaction product of    the reaction (B) with a compound (B);-   compound (B) is selected from the group consisting of NaCN, KCN,    Si(R9)(R10)(R11)CN, HCN, tetrabutylammonium cyanide, 1-cyano    benzotriazole and triselenium dicyanide and mixtures thereof;-   R9, R10 and R11 are identical or different and independently from    each other selected from the group consisting of C₁₋₄ alkyl and    phenyl.

Formula (IV) comprises all possible tautomeric forms of compound offormula (IV).

Formula (V) comprises all possible tautomeric forms of compound offormula (V).

Base (B), compound of formula (IV) and compound of formula (V) can beadded in any sequence.

Preferably, base (B) is used to deprotonate the CH₂ moiety of thecompound of formula (V).

Preferably, deprotonated compound of formula (V) is added to compound offormula (IV) or vice versa.

The reaction product of the reaction (B), which is reacted with acompound (B) in the reaction (B-add) of step (B) after the reaction (B),is a compound of formula (II-R1-IV);

wherein R1-IV is defined as above, also with all its preferredembodiments.

Formula (II-R1-IV) comprises all possible tautomeric forms of compoundof formula (II-R1-IV).

Compounds of formulae (IV) and (V) are known compounds and can beprepared by known methods.

Preferably, R1-IV and R3 are identical and are Cl or Br.

Preferably, R1-IV and R3 are Cl.

Preferably, R4, R5, R6 are identical or different and independently fromeach other selected from the group consisting of cyclohexyl, phenyl,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl and (CH₂)_(m)N(R12)R13;

-   R12 and R13 are identical or different and independently from each    other selected from the group consisting of H, methyl, ethyl,    n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl;-   m is 2, 3 or 4;-   R14 and R15 are methyl.

More preferably, R4, R5, R6 are identical or different and independentlyfrom each other selected from the group consisting of cyclohexyl,phenyl, methyl, ethyl, n-propyl, iso-propyl and (CH₂)_(m)N(R12)R13;

-   R12 and R13 are identical or different and independently from each    other selected from the group consisting of H, methyl, ethyl,    n-propyl and iso-propyl;-   m is 2, 3 or 4;-   R14 and R15 are methyl.

Even more preferably, R4, R5, R6 are selected from the group consistingof cyclohexyl, phenyl, methyl, ethyl, n-propyl, iso-propyl and(CH₂)_(m)N(R12)R13;

-   R12 and R13 are selected from the group consisting of H, methyl,    ethyl, n-propyl and iso-propyl;-   m is 2;-   R14 and R15 are methyl.

Especially, R4, R5, R6 are methyl or ethyl and (CH₂)_(m)N(R12)R13;

R12 and R13 are H, methyl or ethyl;

m is 2;

R14 and R15 are methyl.

Base (B) must have the capability to deprotonate the CH₂ moiety of thecompound of formula (V). Preferably, the pKa value of the correspondingprotonated form of base (B) is from 5 to 40, more preferably from 6 to18, even more preferably from 6 to 13.

Preferably, base (B) is selected from the group consisting ofN(R4)(R5)R6, 1,4-diazabicyclo[2.2.2]octane, a hexamethyldisilazide, aC₁₋₄ alkoxide salt of, a C₁₋₁₀ carboxylate salt of, a carbonate salt of,a hydrogen carbonate salt of, a phosphate salt of, amonohydrogenphosphate salt of or a dihydrogenphosphate salt of Na, of Kor of Li, 1,8-diazabicyclo[5.4.0]undec-7-ene, NaNH₂, KNH₂, NaH, KH,CaH₂, pyridine, pyridine substituted with 1 or 2 independently selectedidentical or different C₁₋₂ alkyl residues, N,N-dimethyl-4-pyridinamine,morpholine, 4-methylmorpholine, 1-methylpiperidine, imidazol,benzimidazol, 2-methylimidazole, 4-methylimidazole, 2-ethylimidazole,2-ethyl-4-methylimidazole, 2-isopropylimidazole, 2-phenylimidazole,4-phenylimidazole, picoline, CsCO₃, NaOH, KOH, Ca(OH)₂ and mixturesthereof;

with R4, R5 and R6 as defined herein, also with all their preferredembodiments.

More preferably, base (B) is selected from the group consisting ofN(R4)(R5)R6, 1,4-diazabicyclo[2.2.2]octane, a hexamethyldisilazide, aC₁₋₄ alkoxide salt of, a C₁₋₁₀ carboxylate salt of, a carbonate salt of,a hydrogen carbonate salt of, a phosphate salt of, amonohydrogenphosphate salt of or a dihydrogenphosphate salt of Na, of Kor of Li, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, pyridinesubstituted with 1 or 2 independently selected identical or differentC₁₋₂ alkyl residues, N,N-dimethyl-4-pyridinamine, morpholine,4-methylmorpholine, 1-methylpiperidine, imidazol, benzimidazol,2-methylimidazole, 4-methylimidazole, 2-ethylimidazole,2-ethyl-4-methylimidazole, 2-isopropylimidazole, 2-phenylimidazole,4-phenylimidazole, picoline, NaOH, KOH, Ca(OH)₂ and mixtures thereof;

R4, R5, R6 are methyl or ethyl and (CH₂)_(m)N(R12)R13;

R12 and R13 are H, methyl or ethyl;

m is 2;

R14 and R15 are methyl.

Even more preferably, base (B) is selected from the group consisting ofN(R4)(R5)R6, 1,4-diazabicyclo[2.2.2]octane, a hexamethyldisilazide, aC₁₋₄ alkoxide salt of, a C₁₋₁₀ carboxylate salt of, a carbonate salt of,a hydrogen carbonate salt of, a phosphate salt of, amonohydrogenphosphate salt of or a dihydrogenphosphate salt of Na, of Kor of Li, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, pyridinesubstituted with 1 or 2 independently selected identical or differentC₁₋₂ alkyl residues, N,N-dimethyl-4-pyridinamine, morpholine, imidazol,benzimidazol, 2-methylimidazole, 4-methylimidazole, 2-ethylimidazole,2-ethyl-4-methylimidazole, 2-isopropylimidazole, 2-phenylimidazole,4-phenylimidazole, picoline, NaOH, KOH, Ca(OH)₂ and mixtures thereof;

R4, R5, R6 are methyl or ethyl and (CH₂)_(m)N(R12)R13;

R12 and R13 are H, methyl or ethyl;

m is 2;

R14 and R15 are methyl.

Especially, the base (B) is selected from the group consisting of NEt₃,tetramethylethylendiamine and N,N-dimethyl-4-pyridinamine and mixturesthereof.

Preferably, R9, R10 and R11 are identical and are selected from thegroup consisting of C₁₋₄ alkyl.

More preferably, R9, R10 and R11 are methyl.

Also other CN sources, which act as equivalents to those listed forcompound (B), can be used.

Preferably, compound (B) is NaCN or KCN.

Reaction (B) can be done in a solvent (B). Preferably, the solvent (B)is selected from the group consisting of hexanes, heptanes,dichloromethane, dichloroethane, chloroform, carbon tetrachloride,toluene, xylene, mesitylene, dioxane, methyl tert-butyl ether andmixtures thereof.

Preferably, the solvent (B) is dichloromethane.

Preferably, the reaction temperature of reaction (B) is from −78 to 100°C., more preferably from −50 to 50° C., even more preferably from −25 to25° C., especially from −15 to 25° C.

Preferably, the reaction (B) is done at a pressure of from atmosphericpressure to 60 bar, more preferably of from atmospheric pressure to 10bar, even more preferably of from atmospheric pressure to 2 bar,especially at atmospheric pressure.

Preferably, the reaction time of reaction (B) is from 5 min to 24 h,more preferably from 5 min to 12 h, even more preferably from 1 h to 5h, especially from 2 h to 3 h.

Preferably, the amount of compound of formula (V) is from 0.5 to 10 molequivalent, more preferably from 0.9 to 5 mol equivalent, even morepreferably from 0.95 to 1.25 mol equivalent, especially from 0.98 to1.05 mol equivalent, of the mol of compound of formula (IV).

Preferably, the amount of solvent (B) is from 1 to 100 fold, morepreferably from 5 to 50 fold, even more preferably from 5 to 20 fold,especially from 5 to 15 fold, of the weight of compound of formula (IV).

Preferably, the molar amount of base (B) is from 0.5 to 10 fold, morepreferably from 0.95 to 3 fold, of the molar amount of compound offormula (V).

Preferably, the reaction (B) is done under inert atmosphere.

After the reaction (B), the compound of formula (II) can be isolatedfrom the reaction mixture resulting from reaction (B) by standardmethods known to the skilled person such as acidification, filtration,evaporation of volatile components, extraction, washing, drying,concentration, crystallization, distillation and any combinationthereof.

Optionally, any organic phase can be dried, preferably with magnesiumsulphate or sodium sulphate.

Optionally, compound of formula (II) can be separated from the reactionmixture by addition of an acid (B).

Therefore further subject of the invention is a method (B), whichcomprises further a step (ACID);

step (ACID) is done after step (B);

step (ACID) comprises combining the reaction mixture prepared in step(B) with an acid (B).

In step (ACID) the reaction mixture prepared in step (B) can be added toacid (B) or vice versa.

Acid (B) is selected from the group consisting of polymeric sulfonicacid resin, toluene sulfonic acid, HCl, H₂SO₄, citric acid, tartaricacid, acetic acid, ammonium chloride, oxalic acid, phosphoric acid andmixtures thereof, preferably acid (B) is a polymeric sulfonic acidresin.

Preferably, acid (B) is used without water or at least as a mixture withonly a small amount of water, when acid (B) is added to the reactionmixture of step (B), e.g. as gas in case of HCl, without crystal waterin the case of e.g. citric or tartaric acid, or as conc. H₂SO₄ in caseof sulphuric acid.

The water content of acid (B) in this case is preferably 0 to 5% byweight, more preferably 0 to 2.5% by weight, even more preferably 0 to2% by weight, the % by weight being based on the total weight of acid(B).

When the reaction mixture of step (B) is added to acid (B), then acid(B) is preferably used as a mixture with water, and the water content ofacid (B) is preferably 0.5 to 99% by weight.

Preferably, no water is added in step (B). When no water is added instep (ACID), then water or a mixture of acid (B) with water can be addedafter step (ACID).

Preferably, the amount of acid (B) is 0.5 to 10, more preferably 1 to 3,even more preferably 1.2 to 2 mol equivalents in case when acid (B) isnot a polymeric sulfonic acid resin, whereas in case when acid (B) is apolymeric sulfonic acid resin, then acid (B) is used in an amount of 0.5to 10, more preferably 1 to 5, even more preferably 1.3 to 2 molequivalents of sulfonic acid groups of acid (B), the mol equivalentsbeing based on the molar amount of base (B).

Preferably, acid (B) is added in such an amount, that the pH is adjustedto 0 to 7, more preferably 0.5 to 7, even more preferably 1 to 7,especially 1 to 4, more especially 1 to 2.

The polymeric sulfonic acid resin is preferably an acidic cationexchange resin, more preferably a strongly acidic cation exchange resin,for example such as used in heterogeneous acid catalysis.

Preferably, the polymeric sulfonic acid resin has an average molecularweight of from 1000 to 1000000 D; and/or

-   preferably a concentration of acid sites of from 1 to 15, more    preferably of from 1 to 11.6, even more preferably of from 1 to 10,    especially of from 1 to 8, more especially of from 1 to 7    equivalents per kg resin; and/or-   preferably an acid number of from 1 to 650, more preferably of from    1 to 560, even more preferably of from 1 to 450, especially of from    1 to 350, more especially of from 50 to 650, even more especially of    from 1 to 560, in particular of from 50 to 450, more in particular    of from 50 to 350; and/or-   preferably a particle size of from 4 to 800 mesh, more preferably 4    to 400 mesh.

The concentration of acid sites is determined by the Master Test MethodMTM 0232, Edition 1.4, © Rohm and Haas Company, 1998, wherein theCATALYST VOLATILES are determined by the Master Test Method MTM 0126,Edition 1.6, © Rohm and Haas Company, 2000.

The acid number is determined according to DIN EN ISO 3682. For furtherexplanation of the acid number and for its relation to the concentrationof acid sites see “BASF Handbuch Lackiertechnik”, Artur Goldschmidt andHans-Joachim Streitberger, Vincentz Verlag, 2002, ISBN 3-87870-324-4,chapter 2.3.2.2 (pages 272 to 273). According to the teaching therein,an concentration of acid sites of 1 equivalents per kg equals an acidnumber of 56, therefore a concentration of acid sites of 4.7 equivalentsper kg equals an acid number of 263.

Especially, the polymeric sulfonic acid resin is selected from the groupconsisting of sulfonated polystyrene resins, sulfonated polystyreneresins crosslinked with divinyl benzene andpoly(2-acrylamido-2-methyl-1-propanesulfonic acid).

Sulfonated polystyrene resins crosslinked with divinyl benzene are alsocalled divinylbenzene-styrenesulfonic acid copolymer.

One example for a polymeric sulfonic acid resin is Amberlyst® 15 DRY.

After addition of acid (B) the mixture can be filtered,

Preferably, any volatile components of the reaction mixture are removedby evaporation under reduced pressure.

Any concentration is preferably done by distillation, preferably underreduced pressure.

Even more preferably, the reaction mixture is acidified, the organicphase is separated and concentrated.

Especially, acid (B) is a polymeric sulfonic acid resin and solvent (B)is chosen in such a way, that acid (B) is insoluble in solvent (B).Thereby after acidification by addition of the polymeric sulfonic acidresin the reaction mixture can be filtered, thereby filtering off theresin, and the compound is isolated by evaporation of solvent (B).Thereby no water needs to be added.

The compound of formula (II) can be purified by standard methods knownto the skilled person, preferably by crystallization or distillationunder reduced pressure.

Compound of formula (VI) is a known compound and can be prepared byknown methods.

Preferably, compound (C) is Cl₂ or Br₂, more preferably Cl₂.

Even more preferably, compound (C) is Cl₂, R1-IV and R3 are Cl and R1 isCl or CN.

Reaction (C) can be done in a solvent (C). Preferably, the solvent (C)is selected from the group consisting of hexane, heptane,dichloromethane, dichloroethane, chloroform, carbon tetrachloride,toluene, xylene, mesitylene, dioxane, methyl tert-butyl ether andmixtures thereof.

Preferably, the solvent (C) is dichloromethane.

Preferably, the reaction temperature of reaction (C) is from −78 to 100°C., more preferably from −40 to 40° C., even more preferably from −25 to25° C., especially from −20 to 20° C.

Preferably, the reaction (C) is done at a pressure of from atmosphericpressure to 60 bar, more preferably of from atmospheric pressure to 10bar, even more preferably of from atmospheric pressure to 2 bar,especially at atmospheric pressure.

Preferably, the reaction time of reaction (C) is from 1 min to 24 h,more preferably from 1 min to 12 h, even more preferably from 1 min to 6h, especially from 10 min to 2 h.

Preferably, the amount of compound (C) is from 0.9 to 10 mol equivalent,more preferably from 0.95 to 2 mol equivalent, even more preferably from0.98 to 1.05 mol equivalent, of the mol of compound of formula (VI).

Preferably, the amount of solvent (C) is from 1 to 100 fold, morepreferably from 5 to 50 fold, even more preferably from 5 to 20 fold,especially from 5 to 15 fold, of the weight of compound of formula (VI).

Preferably, the reaction (C) is done under inert atmosphere.

After the reaction (C), the compound of formula (IV) can be isolatedfrom the reaction mixture resulting from reaction (C) by standardmethods known to the skilled person such as acidification, filtration,evaporation of volatile components, extraction, washing, drying,concentration, crystallization, distillation and any combinationthereof.

Compound of formula (IV) can also be not isolated, but used directly forthe next reaction without isolation.

Optionally, any organic phase can be dried, preferably with magnesiumsulphate or sodium sulphate.

Preferably, method (B) comprises further a step (A), with method (B) asdefined herein, also with all its preferred embodiments;

-   step (A) is done after step (B);-   step (A) comprises a reaction (A) of compound of formula (II), which    has been prepared in step (B), with a compound of formula (III) to    provide compound of formula (I);

R2 is C₁₋₄ alkyl.

Formula (I) comprises all possible tautomeric forms of compound offormula (I).

Formula (II) comprises all possible tautomeric forms of compound offormula (II).

Possible tautomers of compound of formulae (I) are inter alia compoundof formula (I-a), compound of formula (I-b) and compound of formula(I-c).

Possible tautomers of compound of formulae (II) are inter alia compoundof formula (II-a), compound of formula (II-b) and compound of formula(II-c).

Preferably, R1 is Cl or CN.

More preferably, compound (C) is Cl₂, R1-IV and R3 are Cl and R1 is Clor CN.

Preferably, R2 is selected from the group consisting of methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl;

more preferably, R2 is ethyl or tert-butyl;

even more preferably, R2 is tert-butyl.

Especially, R1 is Cl or CN, and R2 is tert-butyl.

More especially, R1 is Cl or CN, R2 is tert-butyl, compound (C) is Cl₂and R1-IV and R3 are Cl.

Reaction (A) can be done in a solvent (A). Any solvent that does notinterfere with the reaction and has a boiling point of preferably 50° C.or more can in principle be used.

Preferably, solvent (A) is selected from the group consisting of hexane,heptane, dichloromethane, dichloroethane, chloroform, toluene, xylene,mesitylene, dioxane, N,N-di-C₁₋₄ alkyl C₁₋₄ monocarboxamide, di-C₁₋₂alkyl sulfoxide and mixtures thereof.

Preferably, the compound of formula (III) serves also as solvent (A).

Preferably, the compound of formula (III) serves also as solvent (A) andno further solvent (A) is used.

Preferably, the reaction temperature of reaction (A) is from −40 to 180°C., more preferably from 20 to 100° C., even more preferably from 20 to150° C. especially from 30 to 90° C., more especially from 40 to 85° C.

Preferably, the reaction (A) is done at a pressure of from atmosphericpressure to 60 bar, more preferably of from atmospheric pressure to 10bar, even more preferably of from atmospheric pressure to 2 bar,especially at atmospheric pressure.

Preferably, the reaction time of reaction (A) is from 5 min to 48 h,more preferably 5 min to 24 h, more preferably from 1 h to 8 h, evenmore preferably from 1 h to 3 h.

Preferably, the amount of compound of formula (III) is from 1 to 200 molequivalent, more preferably from 1 to 100 mol equivalent, even morepreferably from 1 to 50 mol equivalent, of the mol of compound offormula (II).

Preferably, the amount of solvent (A) is from 0.1 to 100 fold, morepreferably from 0.1 to 50 fold, even more preferably from 0.1 to 20fold, especially from 0.1 to 10 fold, of the weight of compound offormula (II).

Usually, the amount of solvent (A) is at least 2 or 5 fold of the weightof compound of formula (II), therefore further possible ranges arepreferably 2 to 100 fold, more preferably from 2 to 50 fold, even morepreferably from 2 to 20 fold, especially from 2 to 10 fold, of theweight of compound of formula (II); or

preferably 5 to 100 fold, more preferably from 5 to 50 fold, even morepreferably from 5 to 20 fold, especially from 5 to 10 fold, of theweight of compound of formula (II).

If compound of formula (III) is not used as solvent, then preferably theamount of compound of formula (II) is from 1 to 2 mol equivalent, morepreferably from 1 to 1.5 mol equivalent, even more preferably from 1.1to 1.5 mol equivalent, of the mol of compound of formula (II).

Reaction (A) can be done in the presence of an acid (A).

Preferably, acid (A) is selected from the group consisting of polymericsulfonic acid resin, toluene sulfonic acid, HCl, H₂SO₄, citric acid,tartaric acid, acetic acid, ammonium chloride, oxalic acid, phosphoricacid and mixtures thereof, preferably acid (A) is a HCl.

Preferably, the amount of acid (A) is from 0.1 to 100 fold, morepreferably from 0.1 to 50 fold, even more preferably from 0.1 to 20fold, especially from 0.1 to 10 fold, of the weight of compound offormula (II).

Acid (A) is used without water or as a mixture with water, eg. asaqueous HCl or as aqueous H₂SO₄ or cone. H₂SO₄.

The water content of acid (A) is preferably 0 to 99% by weight, the % byweight being based on the total weight of acid (A).

Preferably, the reaction (A) is done under inert atmosphere.

After the reaction (A), the compound of formula (I) can be isolated fromthe reaction mixture resulting from reaction (A) by standard methodsknown to the skilled person such as filtration, evaporation of volatilecomponents, extraction, washing, drying, concentration, crystallization,distillation and any combination thereof.

Optionally, colored impurities can be removed by conventionally knowntreatment with charcoal, eg by treatment with charcoal of the reactionmixture from reaction (B) and/or from reaction (A).

Optionally, any organic phase can be dried, preferably with magnesiumsulphate or sodium sulphate.

Preferably, any volatile components of the reaction mixture are removedby evaporation under reduced pressure.

Any concentration is preferably done by distillation, preferably underreduced pressure.

The compound of formula (I) can be purified, preferably bycrystallization or distillation under reduced pressure.

Step (ACID) is done after step (B) and before step (A).

Preferably, step (B), optionally step (ACID), and then step (A) are doneconsecutively without isolating compound of formula (II).

Preferably, an optional solvent (B) and an optional solvent (A) areidentical.

More preferably, step (B) and step (A) are done in one pot, and anoptional solvent (B) and an optional solvent (A) are identical.

Preferably, step (C) and step (B) are done consecutively withoutisolating the compound of formula (IV).

Preferably, an optional solvent (C) and an optional solvent (B) areidentical.

More preferably, step (C) and step (B) are done in one pot, and anoptional solvent (C) and an optional solvent (B) are identical.

Preferably, step (C), step (B) and step (A) are done consecutivelywithout isolating the compounds of formulae (IV) and (II).

Preferably, an optional solvent (C), an optional solvent (B) and anoptional solvent (A) are identical.

More preferably, step (C), step (B) and step (A) are done in one pot,and an optional solvent (C), an optional solvent (B) and an optionalsolvent (A) are identical.

In another preferred embodiment, step (ACID) is done after step (B),compound of formula (II) is isolated, and then step (A) is done andsolvent (A) is compound of formula (III); more preferably acid (B) is apolymeric sulfonic acid resin and solvent (B) is chosen in such a way,that acid (B) is insoluble in solvent (B).

Each of the steps (C), (B), (A) and the optional step (ACID) can be donecontinuously in a flow reactor. Steps (C) and (B), or steps (C), (B),(A) and the optional step (ACID) can also be done consecutively andcontinuously in a flow reactor without isolation of any intermediate.

Suitable flow reactors are known in the art, there is no specificrequirement for a suitable flow reactor to carry out any of the steps(C), (B) or (A) continuously.

Further subject of the invention is a method (PREP) for the preparationof a compound selected from the group consisting of compound of formula(X), compound of formula (XI), compound of formula (XII), Rosuvastatinand Atorvastatin;

method (PREP) comprises the step (C) and the step (B);

step (C), step (B) and R are as defined herein, also with all theirpreferred embodiments;

R2 is as defined herein, also with all its preferred embodiments;

R7 is O—C(O)CH₃, OH or CH₂—NH₂.

In one preferred embodiment, method (PREP) comprises also the step(ACID).

In another preferred embodiment, method (PREP) comprises also the step(A).

In another preferred embodiment, method (PREP) comprises also the step(ACID) and the step (A).

Compound of formula (X), compound of formula (XI), compound of formula(XII), compound of formula (XIII), Rosuvastatin and Atorvastatin areknown compounds.

The methods for preparation of compound of formula (X), of compound offormula (XI), of compound of formula (XII), of compound of formula(XIII), of Rosuvastatin and of Atorvastatin using compound of formula(II) as intermediate are known.

The method of the present invention does not necessitate mandatorily theuse of metal derived bases. It provides the compounds of formulae (I)and (II) in high yields and high purities, the compounds have bright,white color. Compound of formula (II) can be isolated after the reactionin an easy way, especially a mixture of an organic and an aqueous phaseseparates in the two phases fast and unambiguously, which facilitatesisolation considerably. Another easy way to isolate the compounds is theaddition of an acid, preferably of an insoluble polymeric sulfonic acidresin, filtration and evaporation of solvent, thereby the use of watercan be omitted.

The method is environmentally uncritical; it does not use toxicsubstances.

Further advantage is the fact, that the disclosed methods can be done attemperature well above −78° C., which are conventionally used inmethods, where the C6 scaffold of compound of formula (I) is built upfrom a reaction of a C4 precursor with an acetic acid ester derivative,for example by aldol condensation and similar reactions.

Further advantages of reaction (A) are the side products: only carbondioxide and acetone are generated as side products, therefore reaction(A) is an environmentally friendly method. The acetone can even beisolated and used for other purposes.

The WO 01/72706 A discloses in examples 1.4 and 1.5 a process comprising6 steps, when calculated from the starting C2 building block, whichcould be applied for the preparation of compound of formula (I), whichis the precursor of BHA: 1. Chloroacetic acid is converted to its acidchloride, 2. then reacted with Meldrunm's acid, 3. then converted byhydrolysis to the respective butyric acid derivative, 4. then againconverted into the acid chloride, 5. reacted a second time withMeldrum's acid and 6. finally converted by esterfication into therespective derivative of compound of formula (I). Two equivalents eachof Meldrum's acid, chlorine, base and alcohol is needed.

The process of the instant invention allows for the preparation ofcompound of formula (I), which is the precursor of BHA in a 4 stepprocess: 1. acetic acid is converted into diketene, 2. diketene isconverted with Cl₂ into the chlorinated butyric acid chloridederivative, 3. then reacted with Meldrum's acid, and 4. finallyconverted by esterfication into compound of formula (I). Only oneequivalent Meldrum's acid, chlorine, base and alcohol are needed.Furthermore, no magnesium or lithium derived bases are necessary as isthe case in the WO 01/72706 A for the process according to scheme-2 oraccording to its step b) of claim 8. Furthermore, a chlorinating agentof the invention is Cl₂, which is inexpensive compared tooxalylchloride, thionylchloride or PCl₅, which are disclosed on page 8of the WO 01/72706 A as possible chlorinating agents. No waste or byproducts such as CO₂, CO, SO₂, SO₃ or phosphor derivatives are producedin the step, when the chlorine is introduced into the precursor.

The process of the invention allows to carry out reaction (C) andreaction (B) consecutively without isolation of the intermediatecompound of formula (IV), the two reaction can be done in the samesolvent and even in one pot.

Continuous reaction mode can easily be applied.

The process of the invention provides for bright, white solids in highyields, the solids are obtained as suspensions which show goodfiltration behaviour.

Compared to WO 01/72706 A, no free acid as intermediate occurs, whichhas naturally an enhanced solubility in water and therefore complicatesits isolation from an organic phase used in the reaction. The process ofWO 01/72706 disclosed in examples 1.4 and 1.5 and scheme-1 starts with afree C2-carboxylic acid and a further free C4 carboxylic acid isisolated as intermediate.

EXAMPLES List of Abbreviations and Raw Materials

-   Amberlyst 15® DRY CAS 39389-20-3; divinylbenzene-styrenesulfonic    acid copolymer, strongly acidic cation exchange resin used as a    heterogeneous acid catalysis; suitable for non-aqueous catalysis,    and has a concentration of acid sites of at least 4.7 eq/kg.    Amberlyst 15® DRY is a product of Rohm and Haas, and was used with    the specifications of August 2005.-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DMAP N,N-Dimethyl-4-pyridinamine-   TMEDA Tetramethylethylendiamine-   eq equivalent(s)

Example 1a

To a solution of a compound of formula (VI) (5.25 g, 62.4 mmol) indichloromethane (50 mL) of −15° C., Cl₂ (4.43 g, 62.4 mmol) was addedduring 30 min at −15° C. A solution of compound of formula (1) wasformed.

This solution of compound of formula (1) was then added within 45 min toa mixture consisting of a compound of formula (V) (9 g, 62.4 mmol), NEt₃(12.65 g, 124.9 mmol) and dichloromethane (50 mL) of −15° C. Theresulting reaction mixture was stirred for 2 h at 0° C. Amberlyst® 15DRY (18 g) was added and the reaction mixture was no longer cooled andallowed to warm to room temperature. The Amberlyst® 15 DRY was filteredoff and aqueous HCl (1M, 100 mL) was added to the filtrate. The phaseswere separated, the organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide the compound of formula(2) as a solid (15.1 g, 92%).

¹H NMR (400 MHz, CDCl₃): δ 1.75 (s, 6H), 4.26 (s, 2H), 4.29 (s, 2H),14.8 (s, 1H)

Example 1b

To a solution of a compound of formula (VI) (17.5 g, 0.21 mol) indichloromethane (90 mL) at −15° C., Cl₂ (14.76 g, 0.21 mol) was addedduring 120 min. The reaction mixture was stirred at −10° C. for 45 min.A solution of compound formula (1) was formed. To this solution ofcompound of formula (1) was then added within 60 min a mixtureconsisting of a compound of formula (V) (30 g, 0.21 mol), NEt₃ (42.13 g,0.42 mol) and dichloromethane (100 mL) of −15° C. The resulting reactionmixture was stirred for 16 h at 0° C. The reaction mixture was acidifiedwith HCl (1M, 100 mL) at room temperature resulting in a dark brownmixture. The two phases could not be observed unambiguously, phaseseparation was therefore done based on calculated expected volumes ofthe expected phases. The phases were separated, the organic phase wasextracted 3 times and was dried over Na₂SO₄. The solids were filteredoff, filtration was slow. The remaining solvent was removed in vacuo toprovide the compound of formula (2) as a dark brown solid (52.2 g, 96%).

Example 1c

To a solution of a compound of formula (VI) (5.25 g, 62.4 mmol) indichloromethane (50 mL) at −15° C., Cl₂ (4.43 g, 62.4 mmol) was addedduring 35 min. A solution of compound formula (1) was formed. Thissolution of compound of formula (1) was then added within 60 min to amixture consisting of a compound of formula (V) (9 g, 62.4 mmol), NEt₃(12.65 g, 124.9 mmol) and dichloromethane (54 mL) at −15° C. Theresulting reaction mixture was stirred for 2.5 h at 0° C. Amberlyst® 15DRY (18 g) was added and stirring was continued for 30 min. The reactionmixture was then allowed to warm to room temperature. The Amberlyst® 15DRY was filtered off; the reaction mixture was filtered over Celite® andfinally concentrated to dryness to yield the compound of formula (2) asa solid (14.2 g, 87%).

Example 1d

To a solution of a compound of formula (VI) (10.5 g, 0.13 mol) indichloromethane (108 mL) at −20° C., Cl₂ (8.86 g, 0.13 mol) was addedduring 105 min. A solution of compound formula (1) was formed. Thissolution of compound of formula (1) was then added within 90 min to amixture consisting of a compound of formula (V) (18 g, 0.13 mol), NEt₃(25.28 g, 0.25 mol) and dichloromethane (110 mL) at −15° C. Theresulting reaction mixture was stirred for 2.5 h at −10° C. Amberlyst®15 DRY (32 g) was added and stirring was continued for 30 min at 0° C.The reaction mixture was then filtered over silica; then acidified withHCl (1M, 150 mL) at 2° C. The phases were separated, the aqueous phasewas extracted with dichloromethane (100 mL) and the combined organicphases were dried over Na₂SO₄, filtered and concentrated under reducedpressure to provide the compound of formula (2) as a solid (28.3 g,86%).

Example 1e

To a solution of a compound of formula (VI) (7.87 g, 0.09 mol) indichloromethane (77 mL) at −15° C., Cl₂ (6.44 g, 0.09 mol) was addedduring 60 min. The reaction mixture was stirred at −10° C. for 75 min. Asolution of compound formula (1) was formed. To this solution ofcompound of formula (1) was then added within 60 min a mixtureconsisting of a compound of formula (V) (10.8 g, 0.07 mol), NEt₃ (16.68g, 0.16 mol) and dichloromethane (80 mL) of −15° C. The resultingreaction mixture was stirred for 16 h at −10° C. The reaction mixturewas acidified to pH 1 with gaseous HCl (6 g) at 5° C. resulting in ayellow-brownish reaction mixture. Water (120 mL) was added and thephases were separated, and dried over Na₂SO₄. The solvent was removed invacuo to provide the compound of formula (2) as a yellow solid (19.7 g,80%).

Example 1f

To a solution of a compound of formula (VI) (7.87 g, 0.09 mol) indichloromethane (77 mL) at −15° C., Cl₂ (6.44 g, 0.09 mol) was addedduring 60 min. The reaction mixture was stirred at −10° C. for 75 min. Asolution of compound formula (1) was formed. To this solution ofcompound of formula (1) was then added within 60 min a mixtureconsisting of a compound of formula (V) (10.8 g, 0.07 mol), NEt₃ (16.68g, 0.16 mol) and dichloromethane (80 mL.) of −15° C. The resultingreaction mixture was stirred for 16 h at −10° C. The reaction mixturewas acidified to pH 1 with conc. H₂SO₄ (13.3 g) at 5° C. resulting in ayellow brownish mixture. Water (120 mL) was added and the phases wereseparated, and dried over Na₂SO₄. The solvent was removed in vacuo toprovide the compound of formula (2) as a brown solid (16.3 g, 66%).

Example 1g

To a solution of a compound of formula (VI) (39.4 g, 0.469 mol) indichloromethane (340 mL) at −15° C., Cl₂ (33.3 g, 469 mol) was addedduring 120 min. The reaction mixture was stirred at −10° C. for 180 min.A solution of compound formula (1) was formed. To this solution ofcompound of formula (1) was then added within 120 min a mixtureconsisting of a compound of formula (V) (52 g, 0.361 mol), TMEDA (83.9g, 0.722 mol) and dichloromethane (340 mL) of −5° C. The resultingreaction mixture was stirred for 4 h at −5° C. The reaction mixture wastransferred into aqueous solution of HCl (5% by weight of HCl, based onthe total weight of the aqueous solution of HCl, 658 g) at 5° C.resulting in a yellow brownish mixture with a pH below 2. After thephases were separated, the solvent was removed in vacuo to provide thecompound of formula (2) as a brown solid with a purity of 80% (101 g,86% yield).

Example 2a

A mixture of compound of formula (2) (7.5 g, 28.3 mmol), preparedaccording to example 1, and tert-butanol (75 mL, 0.81 mol) was stirredat reflux for 2.5 h. The resulting reaction mixture was filtered oversilica and concentrated under reduced pressure to provide compound offormula (3) (6.4 g, 96%).

¹H NMR (400 MHz, CDCl₃): ratio of an enol form (-ef)/a keto form(-kt)=86:14 (area:area); δ 1.48 (s, 9H-ef), 1.49 (s, 9H-kf), 3.31 (s,2H-ef), 3.49 (s, 2H-kf), 3.92 (s, 2H-kf), 4.06 (s, 2H-ef), 4.20 (s,2H-kf), 5.97 (s, 1H-ef)

Example 2b

A mixture of compound of formula (2) (5.2 g, 19.8 mmol), preparedaccording to example 1, and tert-butanol (52 mL, 0.55 mol) was stirredat reflux for 2.5 h. The resulting reaction mixture was concentratedunder reduced pressure to provide compound of formula (3) (4.5 g, 97%).

Example 2c

A mixture of compound of formula (2) (20 g, 76 mmol), prepared accordingto example 1, tert-butanol (56 g, 0.76 mol) and p-toluene sulfonic acidmonohydrate (0.66 g, 4 mmol) was stirred at 50° C. for 3.5 h. Theresulting reaction mixture was dissolved in DCM (150 ml) and washed withwater (150 ml). The organic phase was mixed with water (150 ml), aqueousNaOH (25% w/w) was added until the pH was 8.0 to 9.0, after phaseseparation aqueous 0.5 N HCl was added until the pH was 2.5 to 3.5, andthe mixture was concentrated under reduced pressure to provide compoundof formula (3) (14 g, yield of 63%).

1.-20. (canceled)
 21. A method (PREP) for the preparation of a compoundselected from the group consisting of a compound of formula (X), acompound of formula (XI), a compound of formula (XII), Rosuvastatin andAtorvastatin;

method (PREP) comprises the step (C) and the step (B); step (B) is doneafter step (C); step (C) comprises a reaction (C) of a compound offormula (VI) with a compound (C) to provide a compound of formula (IV);

the compound (C) is selected from the group consisting of Cl₂, Br₂ andClBr; step (B) comprises a reaction (B) of the compound of formula (IV),which has been prepared in step (C), with a compound of formula (V) inthe presence of a base (B) to provide a compound of formula (II);

R1 is selected from the group consisting of Cl, Br and CN; R1-IV and R3are identical and are Cl or Br; R2 is a C₁₋₄ alkyl; base (B) is selectedfrom the group consisting of N(R4)(R5)R6, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, pyridine substituted with1 or 2 independently selected identical or different C₁₋₂ alkylresidues, N,N-dimethyl-4-pyridinamine, morpholine, 4-methylmorpholine,1-methylpiperidine, imidazol, benzimidazol, 2-methylimidazole,4-methylimidazole, 2-ethylimidazole, 2-ethyl-4-methylimidazole,2-isopropylimidazole, 2-phenylimidazole, 4-phenylimidazole, picoline,and mixtures thereof; R4, R5, R6 are identical or different andindependently from each other selected from the group consisting of H,C₁₋₁₅ alkyl, C₅₋₆ cycloalkyl, (C(R16)R17)_(m)N(R12)R13 and phenyl, withthe proviso, that at least one of the residues R4, R5 or R6 is not H; R7is O—C(O)CH₃, OH or CH₂—NH₂; R12 and R13 are identical or different andindependently from each other H or C₁₋₁₅ alkyl; m is 2, 3, 4, 5 or 6;R16 and R17 are identical or different and independently from each otherselected from the group consisting of H, methyl and ethyl; with theproviso, that if R1 or R7 is CN, then step (B) comprises additionally areaction (B-add), the reaction (B-add) is done after the reaction (B),of the reaction product of the reaction (B) with a compound (B);compound (B) is selected from the group consisting of NaCN, KCN,Si(R9)(R10)(R11)CN, HCN, tetrabutylammonium cyanide, 1-cyanobenzotriazole and triselenium dicyanide and mixtures thereof; R9, R10and R11 are identical or different and independently from each otherselected from the group consisting of C₁₋₄ alkyl and phenyl.
 22. Themethod (PREP) according to claim 21, wherein method (PREP) comprises astep (ACID); step (ACID) is done after step (B); step (ACID) comprisescombining the reaction mixture prepared in step (B) with an acid (B);acid (B) is selected from the group consisting of polymeric sulfonicacid resin, toluene sulfonic acid, HCl, H₂SO₄, citric acid, tartaricacid, acetic acid, ammonium chloride, oxalic acid, phosphoric acid andmixtures thereof.
 23. The method (PREP) according to claim 22, whereinacid (B) is a polymeric sulfonic acid resin.
 24. The method (PREP)according to claim 21, wherein R1-IV and R3 are Cl.
 25. The method(PREP) according to claim 21, wherein base (B) is selected from thegroup consisting of NEt₃, tetramethylethylendiamine andN,N-dimethyl-4-pyridinamine and mixtures thereof.
 26. The method (PREP)according to claim 21, wherein base (B) is selected from the groupconsisting of pyridine, pyridine substituted with 1 or 2 independentlyselected identical or different C₁₋₂ alkyl residues, morpholine,4-methylmorpholine, 1-methylpiperidine, imidazol, benzimidazol,2-methylimidazole, 4-methylimidazole, 2-ethylimidazole,2-ethyl-4-methylimidazole, 2-isopropylimidazole, 2-phenylimidazole,4-phenylimidazole, picoline, and mixtures thereof.
 27. The method (PREP)according to claim 21, wherein R4, R5, R6 are identical or different andindependently from each other selected from the group consisting ofcyclohexyl, phenyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl and (CH₂)_(m)N(R12)R13; R12 and R13 areidentical or different and independently from each other selected fromthe group consisting of H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl and tert-butyl; m is 2, 3 or
 4. 28. The method(PREP) according to claim 21, wherein R9, R10 and R11 are identical andare selected from the group consisting of C₁₋₄ alkyl.
 29. The method(PREP) according to claim 21, wherein compound (B) is NaCN or KCN. 30.The method (PREP) according to claim 21, wherein reaction (B) is done ina solvent (B); solvent (B) is selected from the group consisting ofhexanes, heptanes, dichloromethane, dichloroethane, chloroform, carbontetrachloride, toluene, xylene, mesitylene, dioxane, methyl tert-butylether and mixtures thereof.
 31. The method (PREP) according to claim 21,wherein compound (C) is Cl₂ or Br₂.
 32. The method (PREP) according toclaim 21, wherein reaction (C) is done in a solvent (C), solvent (C) isselected from the group consisting of hexane, heptane, dichloromethane,dichloroethane, chloroform, carbon tetrachloride, toluene, xylene,mesitylene, dioxane, methyl tert-butyl ether and mixtures thereof. 33.The method (PREP) according to claim 21, wherein compound (C) is Cl₂,R1-IV and R3 are Cl and R1 is Cl or CN.
 34. The method (PREP) accordingto claim 21, wherein method (B) comprises further a step (A); step (A)is done after step (B); step (A) comprises a reaction (A) of compound offormula (II), which has been prepared in step (B), with a compound offormula (III) to provide compound of formula (I);

R2 is C₁₋₄ alkyl.
 35. The method (PREP) according to claim 34, whereinR1 is Cl or CN.
 36. The method (PREP) according to claim 34, wherein R2is ethyl or tert-butyl.
 37. The method (PREP) according to claim 34,wherein method (B) comprises step (ACID); step (ACID) is done beforestep (A); step (ACID) is done after step (B); step (ACID) comprisescombining the reaction mixture prepared in step (B) with an acid (B);acid (B) is selected from the group consisting of polymeric sulfonicacid resin, toluene sulfonic acid, HCl, H₂SO₄, citric acid, tartaricacid, acetic acid, ammonium chloride, oxalic acid, phosphoric acid andmixtures thereof. step (ACID) is done before step (A).
 38. The method(PREP) according to claim 37, wherein acid (B) is a polymeric sulfonicacid resin.